This invention relates to ophthalmic analgesic agents and in particular to topical ophthalmic agents which are generally used for alleviation of pain sensation in the cornea and conjunctiva due to disease or injury.
Currently, local ophthalmic analgesia is achieved using various anesthetic agents. The anesthetic agents used include topical application of tetracaine hydrochloride, procaine hydrochloride, benoxinate hydrochloride, and proparacaine hydrochloride. Tetracaine, a derivative of para-aminobenzoic acid, is generally applied as a 2.5% solution or by ointment. Procaine is available in concentrations of 1% solution, 2% solution, or 10% solution. Benoxinate, a benzoic acid and related to procaine, is used in a 0.4% solution prior to intraocular pressure measurement. Alcaine, a benzoate, is available in a 0.5% solution. Another drug which has been used as a local ophthalmic anesthetic is cocaine, which is one of the first agents discovered and has been used since the beginning of this century. Extensive pharmacological studies have shown that these drugs when used at therapeutic doses of 5,000 to 20,000 ug/ml exhibit an anesthetic property by completely blocking the neuronal conduction.
Unfortunately, repeated or prolonged application of topical ophthalmic anesthetics has been shown to exert deleterious effects on corneal epithelium, lacrimal glands, mucous production, and cell motility. Furthermore, recent studies have demonstrated that even a single dose of topical anesthetic can cause severe toxicity to the corneal epithelium. Major toxic effects of these drugs include: 1) inhibition of corneal regeneration or re-epithelialization that may result in sloughing of the corneal epithelium, which then exposes the corneal stroma to subsequent destructive effects of pathogenic microorganisms, causing corneal ulcers; 2) alteration in lacrimation and mucous adherence causing decrease in stability of the precorneal tear film; 3) increase in corneal permeability and swelling which results in loss of corneal transparency; and 4) altering corneal epithelial cytoskeletal elements (actin, myosin), which causes disruption of cell motility. Other adverse effects include allergic dermatitis which is seen in sensitive patients. Thus, the profound anesthetic property exhibited by these drugs severely limits their application as topical ophthalmic analgesics. In fact, following application of these topical anesthetics the loss of corneal sensitivity is so profound that some patients inadvertently injure their corneas without being aware of the extent of the self-injury. From the therapeutic standpoint, the outcome of such therapy seems as painful as giving no drug at all. Clearly, it seems that local analgesia can not be achieved by these anesthetics without impairing the normal function of the eye. Collectively, these inherent problems have limited the use of topical ophthalmic anesthetics for pain relief following corneal abrasion and/or injury.
The need for a truly useful ophthalmic analgesic is even more pressing in that numerous ocular conditions, diseases, and injuries would be treated if a safer formulation was available. An ideal formulation should be composed of an effective analgesic which does not cause any adverse effects or permanent damage to ocular structures. The ideal formulation could be prescribed by physicians for the following ocular conditions: 1) any injury to the eye causing damage to the corneal epithelium and conjunctiva, such as traumatic corneal abrasion, penetration, perforation, acid and alkali burn, or any other chemical burn; 2) any disease causing dry eye syndrome and the subsequent loss of localized or diffused corneal-epithelial cell damages, such as keratoconjunctivitis scica, vitamin A deficiency, abnormalities of the eye lids and eye lashes; 3) eye diseases causing cicatricial changes of the conjunctiva and cornea, such as traucoma; 4) viral infection affecting corneal epithelium and/or stroma, such as Herpes viruses and others; 5) bacterial and fungal infections causing corneal ulcers; and 6) any disease affecting lacrimal glands causing lower tear production. These medications could also permit removal of foreign bodies from the conjunctiva, cornea, and those which are dislodged under the superior lid.
The application of this ideal formulation or analgesic agent may eliminate the unnecessary use of local anesthetics or general anesthesia for the examination of sensitive eyes in some patients. Furthermore, the use of this ideal formulation could facilitate general ophthalmic examinations, such as the use of fundus contact lenses for evaluation of the background of the eye or the angle of the anterior chamber. It could also be used prior to the measurement of intraocular pressure. Additionally, an ideal formulation of an ophthalmic analgesic preparation must not irritate or cause any permanent damage to the ocular structures.
For all these reasons, development of a safe, effective topical fommulation for ophthalmic analgesic is warranted. If a topical formulation exhibits an effective analgesia without damaging the corneal epithelium and without having a profound anesthetic property, it may permit normal regrowth of the epithelial cells without any delay over the denuded areas of the cornea. Such a local analgesic can be used for temporary relief of pains in patients having corneal and conjunctival diseases or injuries, without experiencing the deleterious toxic effects of currently used local anesthetics.
An ophthalmic formulation for topical treatment of an eye comprises an opioid analgesic solution. The ophthalmic formulation comprises an aqueous solution of an opiate agonist, such as morphine, in the range of about 0.01 to about 5 mg/ml (0.01-0.5% by weight), having a physiologic pH close to 7.4 and osmolarity of about 300 milliosmol. The preferred concentration of the opiate agonist in the ophthalmic formulation is in the range of about 0.5 to about 0.8 mg/ml.
Accordingly, it is an object of the invention to provide a topical ophthalmic analgesic formulation which does not impair or damage the corneal epithelial cells or other ocular structures.
It is a further object of the present invention to provide a local ophthalmic analgesic formulation which does not exhibit a profound anesthetic property.
It is a still further object of the present invention to provide a local ophthalmic analgesic formulation for use in treating various corneal and conjunctival injuries and diseases.
It is another object of the present invention to provide a local ophthalmic analgesic formulation to be used prior to the measurement of intraocular pressure.
These and other objects and advantages of the present invention will become apparent to those skilled in the art after considering the following detailed specification in conjunction with the accompanying drawing, wherein: